Regulation of synaptic plasticity and cognitive functions by store-operated Orai1 channels

Ca~(2+)信号介导神经元的许多重要作用，包括递质释放、突触 可塑性和基因转录。在树突棘中，它构成了兴奋的部位 接受突触输入，钙离子升高驱动多种形式的突触可塑性，包括长时程增强(LTP)和脊柱形态发生。长时程增强的机制及其生理机制 结果在神经科学中引起了浓厚的兴趣，研究结果表明， 在大脑中形成学习和信息存储的神经化学基础，并由 许多神经退行性疾病、脑损伤和滥用药物。然而，尽管 LTP的生理现象得到了很好的描述，其潜在的分子 机制还不是很清楚。一个不确定的领域是钙离子进入途径的同一性 参与产生脊椎钙信号以及这些信号通路如何与下游相互作用 信号系统。在这项工作中，我们将调查一个相对较差的贡献 了解由商店操作的Orai1通道形成的认知功能的钙内流途径， 树突棘Ca~(2+)信号和LTP。ORAI1通道已在 免疫细胞，它们刺激从钙依赖的基因表达到 炎性介质的分泌。尽管越来越多的证据表明Orai1高度 在大脑中表达，包括在许多对学习和记忆至关重要的区域，特性 对这些通道及其在大脑中的生理作用知之甚少。我们 假设Orai1通道是树突状细胞产生钙信号的关键机制 并对突触诱发的脊椎内钙离子升高做出重大贡献以调节 突触可塑性和认知。使用缺乏Orai1或其激活剂STIM1和STIM2的小鼠， 我们将通过三个具体目标来解决这一假设：1)评估 与学习、记忆和感觉运动功能相关的认知过程的ORAI1通道 在小鼠模型中。2)研究Orai1通道对LTP的生理贡献， CaMKII激活和AMPA受体插入突触后密度，以及3)检查 突触刺激后树突棘中Orai1通道对钙信号的作用。 总之，这些研究将探讨新的钙离子进入途径在突触可塑性中的作用 和认知功能，并最终促进努力针对Orai1通道开发 认知功能障碍的新疗法。

Ca2+ signaling mediates many essential roles in neurons including transmitter release, synaptic plasticity, and gene transcription. In dendritic spines, which constitute the sites where excitatory synaptic input is received, Ca2+ elevations drive many forms of synaptic plasticity including long-term potentiation (LTP) and spine morphogenesis. The mechanism of LTP and its physiological consequences are of intense interest in neuroscience, driven by findings showing that it likely forms the neurochemical basis of learning and information storage in the brain and is altered by numerous neurodegenerative diseases, brain injuries, and drugs of abuse. However, although the physiological phenomenon of LTP is very well characterized, its underlying molecular mechanism is less understood. One area of uncertainty is the identity of the Ca2+ entry pathways involved in generating spine Ca2+ signals and how these pathways interface with downstream signaling systems. In this work, we will investigate the contributions of a relatively poorly understood Ca2+ influx pathway formed by store-operated Orai1 channels for cognitive function, dendritic spine Ca2+ signaling, and LTP. Orai1 channels have been extensively studied in immune cells where they stimulate processes ranging from Ca2+-dependent gene expression to secretion of inflammatory mediators. Although growing evidence indicates that Orai1 is highly expressed in the brain including in many regions critical for learning and memory, the properties of these channels and their physiological roles in the brain are poorly understood. We hypothesize that Orai1 channels are a key mechanism for generating Ca2+ signals in dendritic spines and make significant contributions to synaptically-evoked Ca2+ rises in spines to regulate synaptic plasticity and cognition. Using mice lacking Orai1 or its activators, STIM1 and STIM2, we will address this hypothesis through three specific goals: 1) evaluate the contributions of Orai1 channels for cognitive processes related to learning, memory, and sensorimotor function in mouse models. 2) investigate the physiological contributions of Orai1 channels for LTP, CaMKII activation, and insertion of AMPA receptors into postsynaptic densities, and 3) examine the role of Orai1 channels for Ca2+ signaling in dendritic spines following synaptic stimulation. Together, these studies will address the role of a novel Ca2+ entry pathway for synaptic plasticity and cognitive function, and ultimately facilitate efforts to target Orai1 channels for developing novel therapeutics for cognitive dysfunctions.